Method of making a medical device with regioselective structure-property distribution

ABSTRACT

A medical device and methods of making the medical device such as a stent having selected regions with different material properties than other regions are disclosed. Selection and modification of the regions may be based on facilitating a desired mechanical behavior and/or therapeutic prophylactic property of the device.

This application is a divisional application of application Ser. No.10/931,853 filed Aug. 31, 2004, now abandoned, and is incorporated byreference herein.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to implantable medical devices and methods ofmaking such devices that have selected regions with different materialproperties than other regions of the device.

2. Description of the State of the Art

This invention relates to generally to medical devices having regionswith different clinical or therapeutic and mechanical requirements.Therefore, the invention may be applied to a diverse array of medicaldevices, including, but not limited to radial expandable endoprostheses,heart valves, bone screws, and suture anchors. For example, radiallyexpandable endoprostheses are adapted to be implanted in a bodily lumen.An “endoprosthesis” corresponds to an artificial device that is placedinside the body. A “lumen” refers to a cavity of a tubular organ such asa blood vessel. A stent is an example of such an endoprosthesis. Stentsare generally cylindrically shaped devices which function to hold openand sometimes expand a segment of a blood vessel or other anatomicallumen such as urinary tracts and bile ducts. Stents are often used inthe treatment of atherosclerotic stenosis in blood vessels. “Stenosis”refers to a narrowing or constriction of the diameter of a bodilypassage or orifice. In such treatments, stents reinforce body vesselsand prevent restenosis following angioplasty in the vascular system.“Restenosis” refers to the reoccurrence of stenosis in a blood vessel orheart valve after it has been treated (as by balloon angioplasty orvalvuloplasty) with apparent success.

The treatment of a diseased site or lesion with a stent involves bothdelivery and deployment of the stent. “Delivery” refers to introducingand transporting the stent through a bodily lumen to a region, such as alesion, in a vessel that requires treatment. “Deployment” corresponds tothe expanding of the stent within the lumen at the treatment region.Delivery and deployment of a stent are accomplished by positioning thestent about one end of a catheter, inserting the end of the catheterthrough the skin into a bodily lumen, advancing the catheter in thebodily lumen to a desired treatment location, expanding the stent at thetreatment location, and removing the catheter from the lumen. In thecase of a balloon expandable stent, the stent is mounted about a balloondisposed on the catheter. Mounting the stent typically involvedcompressing or crimping the stent onto the balloon. The stent is thenexpanded by inflating the balloon. The balloon may then be deflated andthe catheter withdrawn. In the case of a self-expanding stent, the stentmay be secured to the catheter via a retractable sheath or a sock. Whenthe stent is in a desired bodily location, the sheath may be withdrawnallowing the stent to self-expand.

The stent must be able to simultaneously satisfy a number of mechanicalrequirements. First, the stent must be capable of withstanding thestructural loads, namely radial compressive forces, imposed on the stentas it supports the walls of a vessel lumen. In addition to havingadequate radial strength or more accurately, hoop strength, the stentshould be longitudinally flexible to allow it to be maneuvered through atortuous vascular path and to enable it to conform to a deployment sitethat may not be linear or may be subject to flexure. The material fromwhich the stent is constructed must allow the stent to undergo expansionwhich typically requires substantial deformation of localized portionsof the stent's structure. Once expanded, the stent must maintain itssize and shape throughout its service life despite the various forcesthat may come to bear thereon, including the cyclic loading induced bythe beating heart. Finally, the stent must be biocompatible so as not totrigger any adverse vascular responses.

The structure of stents is typically composed of scaffolding thatincludes a pattern or network of interconnecting structural elements orstruts. The scaffolding can be formed from wires, tubes, or sheets ofmaterial rolled into a cylindrical shape. The scaffolding is designed toallow the stent to be radially expandable. The pattern should bedesigned to maintain the longitudinal flexibility and radial rigidityrequired of the stent. Longitudinal flexibility facilitates delivery ofthe stent and radial rigidity is needed to hold open a bodily lumen.

Stents have been made of many materials such as metals and polymers,including biodegradable polymer materials. A medicated stent may befabricated by coating the surface of either a metallic or polymericscaffolding with a polymeric carrier that includes an active agent ordrug. Polymeric scaffolding may also serve as a carrier of an activeagent or drug. In many treatment applications, the presence of a stentin a body may be necessary for a limited period of time until itsintended function of, for example, maintaining vascular patency and/ordrug delivery is accomplished. Therefore, stents fabricated frombiodegradable, bioabsorbable, and/or bioerodable materials such asbioabsorbable polymers may be configured to meet this additionalclinical requirement since they may be designed to completely erodeafter the clinical need for them has ended.

Conventional methods of constructing a stent from a polymer materialinvolves extrusion of a polymer tube based on a single polymer orpolymer blend and then laser cutting a pattern into the tube. Apotential shortcoming of such methods is that material properties of thestent formed by such methods tend not to vary substantially throughoutdifferent regions of the stent. Conventional methods of fabricatingmetallic stents suffer from the same shortcoming. Material propertiesmay include mechanical and thermal properties. Additional materialproperties may also include the absorption rate of a biodegradable stentmaterial and the composition of polymer and active agents or drugsimpregnated into a polymer scaffolding. In addition, conventionalcoating methods also tend to form coatings that have relatively uniformmaterial properties along the surface of a stent.

Due to certain mechanical and clinical requirements, it may beadvantageous for certain material properties to be different indifferent portions of an implantable medical device. It may be desirablefor some portions of a stent to have some mechanical properties,absorption rates, and composition different than in other portions ofthe device. For example, as indicated above, localized regions of astent may have different mechanical requirements due to relatively highstress and strain during use, and, thus may require different mechanicalproperties for the different regions.

SUMMARY OF THE INVENTION

Various embodiments of the present invention include a method ofmanufacturing a stent, comprising: selectively heating a selected regionof a stent made of a polymer to modify a material property in theselected region of the stent that has a variable strain profile underapplied stress, wherein the modification accommodates the variablestrain profile of the stent by reducing or preventing mechanicalinstability when the stent is under applied stress, and wherein thestent is composed of a scaffolding including a network ofinterconnecting struts.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a stent.

FIGS. 2A-C, 3A-3B, and 4A-B depict portions of a stent.

FIG. 5 depicts a schematic plot of the rate of crystallization of apolymer as a function of temperature.

FIGS. 6-7 depict portions of a stent modified by selective applicationof heat.

FIG. 8 depicts a stent in a bodily lumen.

FIGS. 9-10 depict portions of a stent.

FIGS. 11A-11D illustrate coatings deposited over a surface of animplantable medical device.

FIGS. 12-13 depict a controlled deposition system.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, the following terms anddefinitions apply:

The “glass transition temperature,” T_(g), is the temperature at whichthe amorphous domains of a polymer change from a brittle vitreous stateto a solid deformable state at atmospheric pressure. In other words, theT_(g) corresponds to the temperature where the onset of segmental motionin the chains of the polymer occurs. When an amorphous orsemicrystalline polymer is exposed to an increasing temperature, thecoefficient of expansion and the heat capacity of the polymer bothincrease as the temperature is raised, indicating increased molecularmotion. As the temperature is raised the actual molecular volume in thesample remains constant, and so a higher coefficient of expansion pointsto an increase in free volume associated with the system and thereforeincreased freedom for the molecules to move. The increasing heatcapacity corresponds to an increase in heat dissipation throughmovement. T_(g) of a given polymer can be dependent on the heating rateand can be influenced by the thermal history of the polymer.Furthermore, the chemical structure of the polymer heavily influencesthe glass transition by affecting mobility.

“Stress” refers to force per unit area, as in the force acting through asmall area within a plane. Stress can be divided into components, normaland parallel to the plane, called normal stress and shear stress,respectively. Tensile stress, for example, is a normal component ofstress applied that leads to expansion (increase in volume and/orlength). In addition, compressive stress is a normal component of stressapplied to materials resulting in their compaction (decrease in volumeand/or length). Stress may result in deformation of a material, whichrefers to change in length and/or volume. “Expansion” or “compression”may be defined as the increase or decrease in length and/or volume of asample of material when the sample is subjected to stress. “Strain”refers to the amount of expansion or compression that occurs in amaterial at a given stress or load. Strain may be expressed as afraction or percentage of the original length, i.e., the change inlength divided by the original length. Strain, therefore, is positivefor expansion and negative for compression.

Furthermore, a property of a material that quantifies a degree ofdeformation with applied stress is the modulus. “Modulus” may be definedas the ratio of a component of stress or force per unit area applied toa material divided by the strain along an axis of applied force thatresults from the applied force. For example, a material has both atensile and a compressive modulus.

The tensile stress on a material may be increased until it reaches an“ultimate tensile strength” which refers to the maximum tensile stresswhich a material will withstand prior to fracture. The ultimate tensilestrength is calculated from the maximum load applied during a testdivided by the original cross-sectional area. Similarly, “ultimatecompressive strength” is the capacity of a material to withstand axiallydirected pushing forces. When the limit of compressive strength isreached, a material is crushed.

The term “elastic deformation” refers to deformation of an object inwhich the applied stress is small enough so that the object movestowards its original dimensions or essentially its original dimensionsonce the stress is released. However, an elastically deformed polymermaterial may be prevented from returning to an undeformed state if thematerial is below the T_(g) of the polymer. Below T_(g), energy barriersmay inhibit or prevent molecular movement that allows deformation orbulk relaxation. “Elastic limit” refers to the maximum stress that amaterial will withstand without permanent deformation. “Ultimate strain”is the strain at the elastic limit. The term “plastic deformation”refers to permanent deformation that occurs in a material under stressafter elastic limits have been exceeded.

“Elasticity” refers to the ability of a material to deform withoutfailure when subjected to an applied stress. For example, as atemperature of a polymer is increased from below to above its T_(g), itselasticity increases. The elasticity of the polymer increases from arelatively inelastic state to more elastic states. Polymers that have arelatively high elasticity are flexible and have a relatively lowmodulus. Conversely, polymers with relatively low elasticity tend to bebrittle and have a relatively high modulus. Elasticity is, accordingly,a relative term. Between two polymers, whichever one has the lowermodulus has the higher elasticity.

“Neutral axis” refers to a line or plane in a member subjected to astress at which the strain is zero. For example, a beam in flexure dueto stress (e.g., at a top face) has tension on one side (e.g., thebottom face) and compression on the other (e.g., the top face). Theneutral axis lies between the two sides at a location or locations ofzero strain. The neutral axis may correspond to a surface. If the beamis symmetric (in both geometry and materials) the neutral axis is at thegeometric centroid (center of mass) of the beam. The strain increases ineither direction away from the neutral axis.

“Solvent” is defined as a substance capable of dissolving or dispersingone or more other substances or capable of at least partially dissolvingor dispersing the substance(s) to form a uniformly dispersed mixture atthe molecular- or ionic-size level. The solvent should be capable ofdissolving at least 0.1 mg of the polymer in 1 ml of the solvent, andmore narrowly 0.5 mg in 1 ml at ambient temperature and ambientpressure.

Embodiments of medical devices described herein relate to medicaldevices having selected regions with mechanical and/or therapeutic orprophylactic requirements different from other regions of the device.Therefore, such selected regions may have desired mechanical behaviorand/or therapeutic or prophylactic properties different from the otherregions of the device. A therapeutic or prophylactic property refers toa therapeutic or prophylactic effect on a portion of a body arising froman active agent. An active agent can be any substance capable ofexerting a therapeutic or prophylactic effect. These devices may includea diverse array of medical devices, including, but not limited toimplantable medical devices such as radial expandable endoprostheses,heart valves, and bone screws and other medical devices such as sutureanchors.

For example, an implantable medical device may include an underlyingscaffolding or substrate. The substrate may have a polymer-based coatingwith a therapeutic or prophylactic property. The polymer-based coatingmay contain, for example, an active agent or drug for localadministration at a diseased site. The underlying substrate that iscoated can be polymeric, metallic, ceramic, or made from any suitablematerial. Implantable medical device is intended to includeself-expandable stents, balloon-expandable stents, stent-grafts, grafts(e.g., aortic grafts), artificial heart valves, cerebrospinal fluidshunts, pacemaker electrodes, and endocardial leads (e.g., FINELINE andENDOTAK, available from Guidant Corporation, Santa Clara, Calif.). Theunderlying structure or substrate of the device can be of virtually anydesign.

To fabricate a conventional coating, a polymer, or a blend of polymers,can be applied on the stent using techniques known to those havingordinary skill in the art. For example, the polymer can be applied tothe stent by dissolving the polymer in a coating solvent, or a mixtureof solvents, and applying the resulting solution on the stent byspraying, “ink-jet-type” deposition methods, brushing, plasmadeposition, and the like.

Polymers can be biostable, bioabsorbable, biodegradable or bioerodable.Biostable refers to polymers that are not biodegradable. The termsbiodegradable, bioabsorbable, and bioerodable are used interchangeablyand refer to polymers that are capable of being completely degradedand/or eroded when exposed to bodily fluids such as blood and can begradually resorbed, absorbed, and/or eliminated by the body. Theprocesses of breaking down and eventual absorption and elimination ofthe polymer can be caused by, for example, hydrolysis, metabolicprocesses, bulk or surface erosion, and the like. It is understood thatafter the process of degradation, erosion, absorption, and/or resorptionhas been completed, no part of the stent will remain or in the case ofcoating applications on a biostable scaffolding, no polymer will remainon the device. In some embodiments, very negligible traces or residuemay be left behind. For stents made from a biodegradable polymer, thestent is intended to remain in the body for a duration of time until itsintended function of, for example, maintaining vascular patency and/ordrug delivery is accomplished.

The underlying structure or substrate of an implantable medical device,such as a stent can be completely or at least in part be made from abiodegradable polymer or combination of biodegradable polymers, abiostable polymer or combination of biostable polymers, or a combinationof biodegradable and biostable polymers. Additionally, a polymer-basedcoating for a surface of a device can be a biodegradable polymer orcombination of biodegradable polymers, a biostable polymer orcombination of biostable polymers, or a combination of biodegradable andbiostable polymers.

Representative examples of polymers that may be used to fabricate, coat,or modify an implantable medical device include, but are not limited to,poly(N-acetylglucosamine) (Chitin), Chitoson, poly(hydroxyvalerate),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polyorthoester, polyanhydride,poly(glycolic acid), poly(glycolide), poly(L-lactic acid),poly(L-lactide), poly(D,L-lactic acid), poly(D,L-lactide),poly(caprolactone), poly(L-lactide-co-ε-caprolactone), poly(trimethylenecarbonate), polyester amide, poly(glycolic acid-co-trimethylenecarbonate), co-poly(ether-esters) (e.g. PEO/PLA), polyphosphazenes,biomolecules (such as fibrin, fibrinogen, cellulose, starch, collagenand hyaluronic acid), polyurethanes, silicones, polyesters, polyolefins,polyisobutylene and ethylene-alphaolefin copolymers, acrylic polymersand copolymers other than polyacrylates, vinyl halide polymers andcopolymers (such as polyvinyl chloride), polyvinyl ethers (such aspolyvinyl methyl ether), polyvinylidene halides (such as polyvinylidenechloride), polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics(such as polystyrene), polyvinyl esters (such as polyvinyl acetate),acrylonitrile-styrene copolymers, ABS resins, polyamides (such as Nylon66 and polycaprolactam), polycarbonates, polyoxymethylenes, polyimides,polyethers, polyurethanes, rayon, rayon-triacetate, cellulose, celluloseacetate, cellulose butyrate, cellulose acetate butyrate, cellophane,cellulose nitrate, cellulose propionate, cellulose ethers, andcarboxymethyl cellulose. Additional representative examples of polymersthat may be especially well suited for use in fabricating an implantablemedical device according to the methods disclosed herein includeethylene vinyl alcohol copolymer (commonly known by the generic nameEVOH or by the trade name EVAL), poly(butyl methacrylate),poly(vinylidene fluoride-co-hexafluororpropene) (e.g., SOLEF 21508,available from Solvay Solexis PVDF, Thorofare, N.J.), polyvinylidenefluoride (otherwise known as KYNAR, available from ATOFINA Chemicals,Philadelphia, Pa.), ethylene-vinyl acetate copolymers, and polyethyleneglycol.

Examples of active agents include antiproliferative substances such asactinomycin D, or derivatives and analogs thereof (manufactured bySigma-Aldrich 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233; orCOSMEGEN available from Merck). Synonyms of actinomycin D includedactinomycin, actinomycin IV, actinomycin I₁, actinomycin X₁, andactinomycin C₁. The bioactive agent can also fall under the genus ofantineoplastic, anti-inflammatory, antiplatelet, anticoagulant,antifibrin, antithrombin, antimitotic, antibiotic, antiallergic andantioxidant substances. Examples of such antineoplastics and/orantimitotics include paclitaxel, (e.g., TAXOL® by Bristol-Myers SquibbCo., Stamford, Conn.), docetaxel (e.g., Taxotere®, from Aventis S.A.,Frankfurt, Germany), methotrexate, azathioprine, vincristine,vinblastine, fluorouracil, doxorubicin hydrochloride (e.g., Adriamycin®from Pharmacia & Upjohn, Peapack N.J.), and mitomycin (e.g., Mutamycin®from Bristol-Myers Squibb Co., Stamford, Conn.). Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includeaspirin, sodium heparin, low molecular weight heparins, heparinoids,hirudin, argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax ä (Biogen, Inc., Cambridge, Mass.). Examplesof such cytostatic or antiproliferative agents include angiopeptin,angiotensin converting enzyme inhibitors such as captopril (e.g.,Capoten® and Capozide® from Bristol-Myers Squibb Co., Stamford, Conn.),cilazapril or lisinopril (e.g., Prinivil® and Prinzide® from Merck &Co., Inc., Whitehouse Station, N.J.), calcium channel blockers (such asnifedipine), colchicine, proteins, peptides, fibroblast growth factor(FGF) antagonists, fish oil (omega 3-fatty acid), histamine antagonists,lovastatin (an inhibitor of HMG-CoA reductase, a cholesterol loweringdrug, brand name Mevacor® from Merck & Co., Inc., Whitehouse Station,N.J.), monoclonal antibodies (such as those specific forPlatelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), and nitric oxide. An example ofan antiallergic agent is permirolast potassium. Other therapeuticsubstances or agents which may be appropriate agents include cisplatin,insulin sensitizers, receptor tyrosine kinase inhibitors, carboplatin,alpha-interferon, genetically engineered epithelial cells, steroidalanti-inflammatory agents, non-steroidal anti-inflammatory agents,antivirals, anticancer drugs, anticoagulant agents, free radicalscavengers, estradiol, antibiotics, nitric oxide donors, super oxidedismutases, super oxide dismutases mimics,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO),tacrolimus, dexamethasone, ABT-578, clobetasol, cytostatic agents,prodrugs thereof, co-drugs thereof, and a combination thereof. Othertherapeutic substances or agents may include rapamycin and structuralderivatives or functional analogs thereof, such as40-O-(2-hydroxy)ethyl-rapamycin (known by the trade name of EVEROLIMUS),40-O-(3-hydroxy)propyl-rapamycin,40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, methyl rapamycin, and40-O-tetrazole-rapamycin.

A non-polymer substrate of the device may be made of a metallic materialor an alloy such as, but not limited to, cobalt chromium alloy(ELGILOY), stainless steel (316L), high nitrogen stainless steel, e.g.,BIODUR 108, cobalt chrome alloy L-605, “MP35N,” “MP20N,” ELASTINITE(Nitinol), tantalum, nickel-titanium alloy, platinum-iridium alloy,gold, magnesium, or combinations thereof. “MP35N” and “MP20N” are tradenames for alloys of cobalt, nickel, chromium and molybdenum availablefrom Standard Press Steel Co., Jenkintown, Pa. “MP35N” consists of 35%cobalt, 35% nickel, 20% chromium, and 10% molybdenum. “MP20N” consistsof 50% cobalt, 20% nickel, 20% chromium, and 10% molybdenum.

As indicated above, selected regions of a medical device may havedesired mechanical behavior and/or therapeutic or prophylacticproperties different from the other regions of the device. Therefore, itmay be desirable for the selected regions to have certain propertiesdifferent from other regions of the medical device. These materialproperties may include mechanical properties such as modulus andstrength. Certain regions of a stent may have relatively high stress andstrain when the device is under an applied stress during use, and thusmay have different mechanical requirements than regions that experiencerelatively low stress and strain. In addition, for biodegradabledevices, it may be advantageous to have localized regions of a devicewith different absorption rates than other regions. Furthermore, due tocertain therapeutic or prophylactic requirements, it may be desirablefor selected regions of a device to have a concentration and/or types ofactive agents different from other regions. Certain embodiments of amedical device are disclosed herein that may include at least oneselected region having a desired mechanical behavior and/or therapeuticor prophylactic property different than other regions of the device. Atleast one selected region may have been selectively modified to have amaterial property different than the other regions to facilitate thedesired mechanical behavior and/or therapeutic property.

In one embodiment, a desired mechanical behavior may include a desiredresistance to mechanical instability to accommodate a variable strainprofile in the device when under an applied stress during use.Mechanical instability may include failure of the substrate or coatingthat may include tearing or fracture and/or detachment of the coatingfrom the surface of the device. In another embodiment, a desiredmechanical behavior may include a desired rate of degradation andfailure. In another embodiment, a desired therapeutic or prophylacticproperty may include a treatment with a desired concentration or typesof active agent of a bodily region adjacent to a selected region.

The material properties in selected regions may be modified byselectively heating and/or selectively applying a material to a selectedregion of the device. Selectively applying a material may includeforming a coating. In particular, selective application of heat maymodify mechanical properties of a selected region of a device.Selectively applying a material may modify properties of a selectedregion including, but not limited to, mechanical properties such asmodulus and strength; types and concentration of active agents; andabsorption rate.

Medical devices are typically subjected to stress during use, bothbefore and during treatment. “Use” includes manufacturing, assembling(e.g., crimping a stent on balloon), delivery of a stent through abodily lumen to a treatment site, and deployment of a stent at atreatment site. Both a scaffolding or substrate and a coating on ascaffolding experience stress that result in strain in the scaffoldingand/or coating. For example, during deployment, the scaffolding and/orcoating of a stent can be exposed to stress caused by the radialexpansion of the stent body. In addition, the scaffolding and/or coatingmay be exposed to stress when it is mounted on a catheter from crimpingor compression of the stent. These stresses can cause the scaffoldingand/or coating to fracture and the coating to tear and/or detach fromthe scaffolding. Failure of the mechanical integrity of the stent whilethe stent is localized in a patient can lead to serious risks for apatient. For example, there is a risk of embolization caused by a pieceof the polymeric scaffolding and/or coating breaking off from the stent.

Generally, the stress and the resulting strain throughout the structureof a stent are not the same throughout the stent. As indicated above,localized portions of the stent's structure undergo substantialdeformation. It follows that the degree of stress and strain experiencedby various portions of the device may be across a broad spectrum. Someportions may experience no or substantially no stress and strain, whileother portions may experience relatively high stress and strain.Additionally, some regions may experience tensile stress and strain,while others may experience compressive stress and strain. In general,it is advantageous for regions of a stent that experience relativelyhigh stress and strain during use to be more elastic or flexible thanregions that experience relatively low stress and strain.

It is important for a device to be mechanically stable throughout therange of stress and strain experienced throughout the manufacturing,assembly, and particularly during radial adjustment for a stent.Unfortunately, many polymers used for stent scaffoldings and coatings,are relatively brittle or inelastic at biological conditions. This isparticularly true for polymers with a T_(g) above a body temperature. Inthis case, the polymer in the stent never reaches its T_(g), andtherefore, the polymer remains relatively inelastic while in the body.

Polymeric stent scaffoldings and/or coatings having a high drug loadingare especially vulnerable to fracture during and after deployment. Also,active agents impregnated in the polymer can adversely affect themechanical properties and therefore the ultimate performance of thepolymeric coating on the stent. Active agents tend to increase thecrystallinity of a polymer scaffolding and/or coating. As a result,elasticity of the scaffolding and/or coating may be decreased whichmakes the scaffolding and/or coating more susceptible to failure whensubjected to high stress.

However, it may be desirable for certain regions of a device to berelatively stiff or inelastic (high modulus) and strong. Such regionsmay experience relatively low stress and strain during use, but act assupport members that maintain the structural integrity of the device.

It is important for the stent as a whole, as well as individual regionsof the stent, to remain mechanically stable throughout the range ofstress and strain experienced throughout the treatment process. Asindicated above, mechanical instability may include fracture of thescaffolding and/or coating, tearing of the coating, and/or detachment ofthe coating from the scaffolding.

Furthermore, polymer-based scaffoldings and/or coatings may beparticularly vulnerable to mechanical instability during use of animplantable medical device. Polymers, in general, and many polymers usedin scaffoldings and coatings for devices tend to have a relatively highdegree of inelasticity, and, hence have relatively low strength comparedto a metal. Polymers can have an ultimate strain as low as 5% of plasticstrain. In general, the ultimate strain for a polymer is highlydependent on material properties including percent crystallinity,orientation of polymer chains, and molecular weight. Therefore,polymer-based scaffoldings and/or coatings are highly susceptible tofracture, tearing, and/or detachment at regions of a medical devicesubjected to relatively high stress and strain.

Embodiments described herein may be illustrated by a stent. FIG. 1Adepicts an example of a three-dimensional view of a stent 10. The stentmay have a pattern that includes a number of interconnecting elements orstruts 15. The embodiments disclosed herein are not limited to stents orto the stent pattern illustrated in FIG. 1A. The embodiments are easilyapplicable to other patterns and other devices. The variations in thestructure of patterns are virtually unlimited. As shown in FIG. 1A thegeometry or shape of stents vary throughout its structure. A pattern mayinclude portions of struts that are straight or relatively straight, anexample being a section 17. In addition, patterns may include strutsthat include curved or bent portions as in a section 20. Patterns mayalso include intersections of struts with curved or bent portions as insections 25 and 30.

Additionally, a surface of a medical device may also be characterized bythe relative location of the surface with respect to a bodily lumen. Thedevice may include luminal surfaces or outer portions, abluminalsurfaces or inner portions, and surfaces between the luminal andabluminal surfaces. For example, struts 15 of stent 10 include abluminalfaces or surfaces 35, luminal faces or surfaces 40, and side-wall facesor surfaces 45. A strut may also be described by axes, a latitudinalaxis, and a longitudinal axis. FIG. 1B depicts a portion 54 of a strutdepicting a latitudinal axis 50 and a longitudinal axis 55 along astraight section of portion 54. A longitudinal axis 51 on a curvedsection of a strut may be defined as a tangent to a curvature at alocation on the curved section. A corresponding latitudinal axis 56 isperpendicular to longitudinal axis 56. In other embodiments, thelatitudinal cross-section may include any number of faces or be a curvedsurface. In some embodiments, the latitudinal cross-section may includeany number of faces or be a curved surface.

The pattern that makes up the stent allows the stent to be radiallyexpandable and longitudinally flexible. Longitudinal flexibilityfacilitates delivery of the stent and radial rigidity is needed to holdopen a body lumen. The pattern should be designed to maintain thelongitudinal flexibility and radial rigidity required of the stent.

As indicated above, the stress and strain experienced by a medicaldevice when under an applied stress during use is not uniform throughoutthe scaffolding and/or the coating. For instance, the stress and strainexperienced by a stent in a radially expanded state are different invarious portions of the stent. Some portions of a stent pattern may haveno or relatively no strain, while others may have relatively highstrain. Straight or substantially straight sections of struts such assection 17 of stent 10 in FIG. 1 experience no or relatively no strain.However, sections 20, 25, and 30 may experience relatively high strainwhen the stent is expanded or crimped.

FIGS. 2A-C, 3A-B, and 4A-B depict partial planar side views of luminalor abluminal surfaces from a stent. The figures illustrate thenonuniformity of stress and strain in a medical device. FIG. 2A depictsa partial planar side view of a portion 60 from a stent in an unexpandedstate that includes straight sections 65 and a curved section 70 with anangle 85. When a stent undergoes radial expansion, portions of strutsbend resulting in an increase of angle 85 between straight sections 65,as shown in FIG. 2B. FIGS. 2A and 2B depict portion 60 in a plane ofbending. The bending of portion 60 causes no or substantially no strainin straight sections 65. However, the bending of section 60 causesrelatively high stress and strain in most of curved section 70. Aconcave portion 75 of curved section 70 experiences relatively hightensile stress and strain and a convex portion 80 of curved section 70experiences relatively high compressive strain. When a stent is crimped,angle 85 decreases and concave portion 75 experiences relatively highcompressive strain and convex portion 80 experiences relatively hightensile strain. FIG. 2C depicts an expanded view of curved section 70with a neutral axis 72 indicated. The strain along the neutral axis iszero. In the stent, the neutral axis corresponds to a surface of zerostrain. For a strut that is symmetric along its longitudinal andlatitudinal axis, the neutral axis may be a geometric centroidperpendicular to a plane of bending (i.e., perpendicular to the plane ofthe sheet of paper). In the case of portion 70 in FIG. 2C, neutral axis72 runs along the midpoint or center of a latitudinal width 71 of curvedsection 70. Therefore, in a small, narrow region of curved section 70along neutral axis 72, there is zero or relatively low strain.

FIG. 3A depicts a partial planar side view of a portion 90 from a stentin an unexpanded state that includes curved section 105, straightsections 95 at an angle 120, and straight section 100. As shown in FIG.3B, radial expansion of the stent increases angle 120. The stress andstrain in straight sections 95 and 100 is relatively small. Section 105experiences relatively high tensile stress and strain at concave portion110 and relatively high compressive stress and strain at portion 115. Aneutral axis 117 is a surface of zero strain that is the boundarybetween portion 110 and portion 115.

FIG. 4A depicts a partial planar side view of a portion 130 from a stentin an unexpanded state that includes curved section 150, straightsections 135, 140, and 145. Straight sections 135 and 140 are at anangle 155 and straight sections 140 and 145 are at an angle 151. Asshown in FIG. 4B, radial expansion of the stent increases angles 150 and155. The stress and strain in straight sections 135, 140, and 145 isrelatively small. Section 150 experiences relatively high tensile stressand strain at concave portions 160 and relatively high compressivestress and strain at convex portions 156. A neutral axis 152 is asurface of zero strain that is the boundary between portions 156 andportions 160. The description and analysis relating to nonuniformity ofstress and strain in a medical device is not limited to the structuresin FIGS. 2A-C, 3A-B, and 4A-B. Analysis of strain distribution in adevice, or generally any structure, subjected to applied stress may beperformed for a device or structure of virtually any geometry.

In general, material properties, including certain mechanicalproperties, may be modified by heating a material. In particular,heating polymer materials may increase or decrease the modulus of thematerial. Increasing the modulus of a polymer may make the polymerstiffer and stronger, while decreasing the modulus may make the polymermore flexible or less brittle. The modification of mechanical propertiesin polymers due to heating is due to alteration of the degree ofcrystallinity and/or size of crystalline regions in a polymer material.Typically, a higher degree of crystallinity and/or a greater size ofcrystalline regions in a polymer material correspond to a higher modulusand higher strength of the material. Conversely, the more amorphous apolymer material is, the lower the modulus, and hence the more flexiblethe polymer material is.

Furthermore, the manner of modification depends on the temperature rangeto which a polymer material is heated. Heating a polymer material to atemperature below the T_(g) of the polymer does not significantly alterthe molecular structure, and hence, the mechanical properties of thematerial. Below T_(g), energy barriers to segmental motion of the chainsof a polymer inhibit or prevent alteration of molecular structure of apolymer material.

In general, crystallization may occur in a polymer material that isheated to a temperature between T_(g) and the melting temperature,T_(m), of the polymer. As a result, heating a polymer to a temperaturebetween the T_(g) and the T_(m) of the polymer increases the modulus ofthe polymer, which makes it stiffer. FIG. 5 depicts a schematic plot ofthe rate of crystallization of a polymer as a function of temperature.(Rodriguez, F., Principles of Polymer Systems, 2^(nd) ed., McGraw Hill(1982)) FIG. 5 shows that the rate of polymer crystallization increasesas the temperature is increased from below the T_(g) of the polymer oris decreased from above the T_(m) of the polymer. The rate ofcrystallization reaches a maximum 165 somewhere between the T_(g) andthe T_(m). FIG. 5 shows that effectively no crystallization occurs belowthe T_(g) or above the T_(m).

In addition, as indicated above, an amorphous polymer may be formed byheating a polymer material. Above the T_(m), a polymer material is adisordered melt and cannot crystallize and any crystallinity present isdestroyed. Quenching a polymer heated to above the T_(m) to atemperature below the T_(g) of the polymer may result in the formationof a solid amorphous polymer. The resulting amorphous polymer materialmay have a lower modulus and be a more flexible or a less stiff materialthan before heating.

Therefore, certain embodiments of a method of manufacturing animplantable medical device may include selectively heating a selectedregion of a device to modify a material property of the selected regionof the device having a variable strain profile under applied stress. Theselective heating may facilitate a desired resistance to mechanicalinstability to accommodate the variable strain profile on the device soas to reduce or prevent mechanical instability as compared to otherregions on the device that have not been selectively heated. In someembodiments, the selective application of heat may selectively modifymaterial properties of the selected region including, but not limitedto, a tensile and/or compressive strength, a tensile or compressivemodulus, thermal properties, and/or absorption rate of a bioabsorbablepolymer in the region.

In some embodiments, the region may be as small 20 microns in diameter,or more narrowly as small as 30, 40, 50, or 60 microns in diameter. Insome embodiments, the selected region may include a coating on thedevice.

In some embodiments, a selected region may be selectively heated with acontrolled heating system which is described herein. In one embodiment,a controlled heating system may include a laser for heating a selectedregion. Representative examples of lasers that may be used include, butare not limited to, excimer, carbon dioxide, and YAG lasers. In otherembodiments, a selected region may be heated with conduction orconvention. For example, a heated filament may be disposed proximate toor in contact with a selected region. The parameters of a heating methodmay be used to control characteristics of a heated region including, butnot limited to, the temperature, size, shape, and thickness. Forexample, the parameters of laser heating may include, but are notlimited to, the length of a pulse, energy of the beam, and/orcross-sectional size of beam. In addition, the conductive heatingparameters may include, but are not limited to, the temperature of aheated filament, size of a heated filament, heated filament material,and distance of heated filament from region.

In certain embodiments, the device may be a stent including a pattern ofstruts that were formed by laser cutting the pattern into a tube. Heatmay be selectively applied prior to, contemporaneous with, and/orsubsequent to laser cutting the pattern into the tube. It may bedesirable to selectively apply heat prior to forming the pattern in thecase of a fine, intricate stent pattern that has relatively thin struts.Selectively applying heat prior to forming a pattern may inhibit orprevent damage to such fine struts. In addition, selectively applyingheat contemporaneous with forming the pattern may increase manufacturingefficiency.

Furthermore, selective heating may increase the temperature of theselected region to within a range of temperature that materialproperties are altered. In one embodiment, the heating may increase thetemperature to greater than or equal to the T_(g) of the polymer andless than or equal to the T_(m) of the polymer. Other embodiments mayinclude increasing the temperature of the selected region with theapplied heat to greater than the T_(m) of the polymer. As indicated bythe above discussion, the temperature to which the selected region isheated depends on the desired modification of a material property.

In some embodiments, modifying a material property in a selected regionof the device may include decreasing the tensile and/or compressivemodulus. As indicated above, the tensile and/or compressive modulus ofthe selected region may be decreased by increasing the temperature ofthe selected region to greater than or equal to the T_(m) of thepolymer. The temperature of the region may then be decreased to atemperature below the T_(g) of the polymer. In certain embodiments, thetemperature may be decreased by allowing the region to cool throughcontact with the environment at an ambient temperature after heating theregion. Other embodiments may include blowing an inert gas such as air,oxygen, nitrogen, etc. that is less than or equal to an ambienttemperature. A heated selected region may cool rapidly to below theT_(g) of the polymer once heating stops due to a small size of theheated region. In some embodiments, the rate of cooling may influencethe degree of amorphous molecular structure induced in the selectedregion. Allowing the region to cool to a temperature between the T_(g)and T_(m) of the polymer may result in at least some crystallization inthe region. The polymer material may then be quenched to below the T_(g)from that temperature. Therefore, the degree of flexibility induced inthe region may be controlled. In some embodiments, the cooling rate maybe reduced, for example, by blowing a heated inert gas on the region orcooling the region in a heated fluid.

Furthermore, it may be desirable to decrease the tensile and/orcompressive modulus, and thus increase flexibility or decreasingstiffness, of a selected region of a device that has a higher strainthan other regions of the device when the device is placed under anapplied stress during use. For example, as indicated in FIGS. 2A-C,3A-B, and 4A-B, different regions of a strut on a stent experiencedifferent levels of stress and strain during use. For example, aselected region including at least a portion of a curved or bent portionof a strut may be selectively heated to decrease the tensile and/orcompressive modulus. FIG. 6 depicts section 200 of a stent with a curvedportion 210, similar to that shown in FIGS. 2A-C, with struts 205. Heatmay be applied selectively to shaded regions 215 to decrease the tensileand/or compressive modulus, making the regions more flexible. Shadedregions 215 may include portions of abluminal, luminal, and/or side-wallsurfaces of portion 210. In a similar manner, at least a portion ofportion 105 in FIGS. 3A-B and at least a portion of portion 150 in FIGS.4A-B may be selectively heated to decrease the tensile and/orcompressive modulus. In general, according to the methods describedherein, the modulus of any region may be decreased, which increases theflexibility or decreases the stiffness of the region, by selectiveheating at and/or proximate to the region.

In some embodiments, modifying a material property in a selected regionof the device may include increasing the tensile and/or compressivemodulus. As indicated above, the tensile and/or compressive modulus ofthe selected region may be increased by increasing the temperature ofthe selected region to greater than or equal to the T_(g) of the polymerin the region and less than or equal to the T_(m) of the polymer. Thetemperature of the region may then be decreased to a temperature belowthe T_(g) of the polymer. Since the crystallization rate of a polymerdepends on the temperature between the T_(g) and the T_(m) asillustrated in FIG. 5, the degree of modification of material propertiesof a polymer material may be controlled by controlling the temperatureof the region. For example, heating the selected region to a temperatureat or near the maximum rate of crystallization of the polymer may inducemore crystallization in the region, resulting in a stiffer, highermodulus region. In addition, the degree of induced crystallization mayalso be controlled by the rate of cooling of the region.

It may be desirable to increase the tensile and/or compressive modulus,and thus increase stiffness or decrease flexibility, of at least aportion of a section of a device that has a lower strain than anothersection of the device when the device is placed under an applied stressduring use. For example, at least a portion of straight or relativelystraight portion of a strut may be selectively heated to increase thetensile and/or compressive modulus. FIG. 7 depicts portion 220 of astent with struts 225. The tensile and/or compressive modulus of theshaded portions of struts 220 may be increased by selective applicationof heat. Shaded regions 220 may include portions of abluminal, luminal,and/or side-wall surfaces. Generally, the methods described herein maybe used to increase the modulus, and hence increase stiffness ordecrease flexibility, of a selected region by selective heating.

Furthermore, as indicated above, certain embodiments of a medical devicemay include at least one selected region of a device having a desiredtherapeutic or prophylactic property different from other regions of thedevice during use. Some embodiments may include a coating selectivelyapplied on the device to facilitate the desired therapeutic property ofat least one selected region of the device. In an embodiment, a coatingmay be selectively applied to selected region of a medical device usinga controlled deposition system described herein. The system may deposita coating on any region of a stent, which may be as small as 50 microns,or more narrowly as small as 25 microns.

In some embodiments, the desired therapeutic or prophylactic propertymay be a treatment with a desired concentration or types of activeagents of a bodily region adjacent to the selected region. For instance,therapeutic or prophylactic treatment of a lesion in a lumen using astent may be facilitated by having a concentration of active agentsand/or types of active agents on selected regions that are differentthan other regions. The bodily region adjacent to the selected regionmay be treated by the desired types of active agent at a desiredconcentration in a coating on the selected region. For example, in longlesions, the center portion of the lesion may be more diseased than theends of the lesion. The center of the lesion may require more of anactive agent or specific types of active agents than the ends of thelesion. Therefore, a coating on a center portion of a stent may have thedesired active agents with a desired concentration.

FIG. 8 depicts a schematic illustration of a stent 300 deployed in alumen 305. Stent 300 is deployed in lumen 305 at the site of a lesion310. A thickness 315 of lesion 310 varies along an axis 320 of lumen305. FIG. 8 shows that lesion 310 is thickest at a center portion of thelesion and thinner at the end portions of the lesion. Therefore, it maybe desirable to have a higher concentration of active agent or drug atcenter portion 335 of stent 300 than end portions 325 and 330. Inaddition, center portion 335 may require different type(s) of activeagents or drugs than end portions 325 and 330.

Additionally, some embodiments of a medical device may include at leastone selected region of a device having a desired rate of degradation andfailure different from other regions of the device. In certainembodiments, at least one selected region may be selectively coated sothat a coating on at least one selected region has an absorption ratedifferent from a coating on the other regions to facilitate the desiredrate of degradation and failure.

Some embodiments may include a coating on at least one selected regionhaving an absorption rate greater than the other regions. For example,in certain embodiments, a biodegradable stent having differentabsorption rates on some regions may degrade and fail in a moredesirable manner. As discussed above, a bioabsorbable stent is intendedto remain in the body for a limited duration of time until its intendedpurpose has ended. Relatively small particles and/or molecules of stentmaterial are eroded, absorbed, or resorbed due to degradation by bodilyfluids and then are carried away by the bodily fluid. Degradation,erosion, absorption, and resorption of stent material result indegradation of the mechanical properties of the stent. The degradationof stent material may cause mechanical failure which may result instructural-sized portions of the stent separating from one another. Thepresence of such structural-sized portions may cause problems in abodily lumen such as thrombosis and blockage. The smaller the size ofsuch portions and the more uniform the mechanical failure of the stent,the lower the risk of such complications. Therefore, it may beadvantageous to fabricate a stent that fails in a predictable anddesirable manner.

In one embodiment, a relatively fast eroding coating may include, but isnot limited to, poly(DL-lactide-co-glycolide). Poly(DL-lactide) isslower eroding than poly(DL-lactide-co-glycolide). A relatively sloweroding coating may include, but is not limited to, poly(L-lactide),which is slower eroding than poly(DL-lactide).

In one embodiment, a stent may be fabricated having at least one regionthat is relatively weak and susceptible to failure within a certainrange of applied stress. For example, the weak regions(s) may beportions of struts that are thinner than struts in other regions of thestent. The applied stress may correspond to conditions that a stentundergoes during use. The weak region(s) may then be coated with abioabsorbable polymer with an absorption rate that is greater than theabsorption rate of a other regions of the stent. The coating mayincrease the strength of the weak region(s) to withstand the appliedstress of the stent during use.

In one embodiment, coated weak regions may be a plurality of regions ator proximate to intersections of at least two struts of the stent, forexample, portions 25 and 30 in FIG. 1. FIG. 9 illustrates portion 350 ofa strut with struts 355 that includes a region 360 of interconnection ofstruts 355. Region 360 is selectively coated, for example, in shadedregion 365 with a coating that has a faster absorption rate than struts355. Region 365 may include portions of the abluminal, luminal, andsidewall surfaces in region 360.

In other embodiments, at least one region may have a coating with aslower absorption rate than other regions of the device. In someembodiments, the other regions may also have a coating. The coating onat least one region may act to inhibit or delay degradation of themechanical properties of the first section. Since other regions maydegrade faster, the mechanical properties may also degrade at a fasterrate, potentially resulting in mechanical failure of the other regionsbefore at least on region with a slower degradation rate. The otherregions may correspond to regions at or proximate to the intersection ofat least two struts of the stent.

As discussed above, different regions of a medical device may havedifferent mechanical requirements. Certain embodiments of a medicaldevice may include at least one selected region of a device having adifferent resistance to mechanical instability than other regions of thedevice due to a variable strain profile of the device when under appliedstress during use. Mechanical instability may include failure of thesubstrate or coating that may include tearing or fracture and/ordetachment of the coating from the surface of the device. The materialselectively applied to at least one selected region may accommodate thevariable strain profile.

In some embodiments, at least one selected region may have a higherstrain than the other regions when the device is under an applied stressduring use. It may be desirable for at least one selected region to havea higher elasticity, or lower modulus than other regions of the device.A region with a higher elasticity may have a greater resistance tomechanical stability than the other regions.

In one embodiment, the selectively applied material may include aplasticizer that lowers the modulus of at least one selected region. Insome embodiments, the material may include a polymer with a lowermodulus than other regions of the device. In other embodiments, theselectively applied material may be a coating with a lower modulus thana coating on other regions of the device. For example, the coating mayhave a primer layer and a reservoir layer.

A relatively flexible, low modulus polymer may include, but is notlimited to, poly(L-lactide-co-ε-caprolactone). A relatively stiff, highmodulus polymer may include, but is not limited to, poly(L-lactide) andpoly(glycolide).

As discussed above and illustrated in FIGS. 2A-C, 3A-B, 4A-B, at leastone selected region may correspond to a curved or bent portion of astrut and other regions may correspond to a straight or relativelystraight portion of a strut. The mechanical instability may includefracture of the coating and/or detachment of the coating from a surfaceof the first section. A coating with a greater resistance to mechanicalinstability may include, but is not limited to, a greater resistance tostrain, a lower tensile and/or compressive modulus (greater flexibilityor elasticity), and better adhesion properties. FIG. 10 depicts aportion 400 of a stent similar to that shown in FIGS. 2A-C. Portion 400includes struts 405 and a curved portion 410. Curved portion 410 isselectively coated in shaded region 415, which may include abluminal,liminal, and sidewall surfaces of portion 410.

As indicated above, it may be desirable for certain regions of a deviceto be relatively stiff or inelastic (high modulus) and strong.Therefore, the coating may include a relatively high modulus polymersuch as poly(L-lactide) or poly(glycolide). Such regions may experiencerelatively low stress and strain during use, but act as support membersthat maintain the structural integrity of the device. Therefore, it maybe desirable to selectively apply a coating with a relatively highmodulus and/or strength on such regions.

In some embodiments, the selectively applied material on at least oneselected region may include a polymer, a plasticizer, a primer, asolvent, and/or a bioactive agent or drug. For instance, the coating maybe polymeric carrier for a bioactive agent for use in delivery of theagent to a diseased site in a lumen. In addition, a plasticizer incoating may increase the flexibility of the coating. Also, a drugdelivery coating with primer layer may improve the adhesion propertiesof a coating, inhibiting or preventing fracture and/or detachment of thecoating form the surface of a substrate. However, it may be desirable tolimit the use of different or modified coating material to higher strainportions of the device to limit exposure of such additional componentsto a body.

In certain embodiments, the coating on the at least one selected regionmay inhibit or prevent mechanical instability of a substrate of amedical device. The coating may include a relatively flexible, lowmodulus, elastomeric polymer such as poly(L-lactide-co-trimethylenecarbonate), or poly(D,L-lactic acid)-polyethylene glycol-poly(D,L-lacticacid) tri-block copolymer. A relatively flexible polymer coating mayinhibit or prevent mechanical instability of a substrate in higherstrain regions of a medical device.

Additionally, it may be desirable to have a lower concentration ofactive agents in a coating in a high strain region of a medical device.It is known that the presence of an active agent in a polymer carrier ofa coating tends to increase the crystallinity of the polymer carrier.The increased crystallinity may increase the modulus of the coatingwhich decreases the elasticity of the coating. As the elasticity of thecoating decreases the coating becomes more susceptible to fracture anddetachment from a substrate. As discussed above, certain regions of adevice may experience higher stress and strain than other regions.Therefore, it may be desirable for a selected high strain region to havea lower concentration of active agent than other regions. As discussedabove and illustrated in FIGS. 2A-C, 3A-B, 4A-B, a high strain regionmay correspond to a curved or bent portion of a strut and a secondsection may correspond to a straight or relatively straight portion of astrut of a stent.

As indicated above, the resistance to mechanical instability may beincreased by including a plasticizer in the polymer. In general, a“plasticizer” is a chemical additive that increases the elasticity of apolymer. A plasticizer, which is usually a low molecular weightnonvolatile molecule, can be dissolved with a polymer material beforethe applying the material to a device. An active agent may also act as aplasticizer.

It is desirable for a plasticizer for use in applying to a medicaldevice to be biocompatible and non-volatile or substantiallynonvolatile. Low volatility is important since diffusion of aplasticizer through a vapor phase into other phases or componentsproximate to an implantable device may influence the effectiveness andsafety of the device.

In addition, it is not desirable for a plasticizer to substantially orsignificantly affect the drug release kinetics or drug stability ofactive agents in a coating. However, it may be advantageous for aplasticizer to change the degradation rate of a biodegradable polymer ina polymer coating.

In one embodiment, a plasticizer can include low molecular weightoligomers of monomers forming a biodegradable polymer. For example, theoligomer can be a dimer, trimer, tetramer or oligomer of lactic acid,which forms PDLL or poly(D,L-lactic acid) (PDLLA). Some exemplary lowmolecular weight plasticizers may include cyclic or linear oligomers ofglycolic acid, lactic acid, 3-hydroxypropanoic acid, 3-hydroxybutyricacid, 4-hydroxybutyric acid, 3-hydroxyvalerate, 4-hydroxyvalerate,5-hydroxyvalerate, 3-hydroxyhexanoate, 4-hydroxyhexanoate, and5-hydroxyhexanoate. Other exemplary plasticizers may include dimers ortrimers of lactic acid. Lactic acid can be racemic or enantiomeric in Dor L form. In one embodiment, the plasticizer is an oligomer ofpoly(D,L-lactic acid) (PDLLA) having a molecular weight in the rangefrom 1000 Daltons to 5,000 Daltons. The low molecular weight oligomerscan be formed by methods documented in the art (see, for example, see,for example, Michael Smith, Organic Synthesis, 2^(nd) Edition,McGraw-Hill, 2001).

In another embodiment, the plasticizer can be a fatty acid. The fattyacid can be synthetic or naturally occurring fatty acids. The fatty acidcan be liquid or solid. Representative natural fatty acids include, butare not limited to, palmitoleic acid, lauric acid, oleic acid, linoleicacid, and arachidonic acid. Representative synthetic fatty acidsinclude, for example, C6-C15 alkanoic acids such as heanoic acid,heptanoic acid, or octanoic acid. Additionally, plasticizers may alsoinclude esters of the fatty acids. It is believed that fatty acid estersdo not influence the polymer degradation kinetics of the coating polymeror stability of the drug in a drug-delivery coating. Representativeester plasticizers may include the ethyl, propyl, and butyl ester ofoleic acid. In addition, plasticizers may be a glyceride, such as amono, di and triglyceride. The glycerides can be natural glycerides orsynthetic glycerides and can contain any of the fatty acids describedabove. For example, most naturally occurring triglycerides containstearate, palmitate, linoleic, oleic fatty facid, or a mixtures thereof.Further representative plasticizers may include synthetic or naturallyoccurring fatty alcohols including, but not limited to, fatty alcoholsdescribed in the FDA GRAS (generally recognized as safe) list.Additional representative examples of plasticizers may include citricacid esters for poly(L-lactide), lactide or lactic acid monomer such asethyl lactate, a polyalkylene glycol such as polyethylene glycol (PEG),or a polyalkylene oxide.

Furthermore, as discussed above, the resistance to mechanical stabilityof a coating on a selected region of a medical device may be increasedby enhancing the adhesion properties of the coating. In someembodiments, the resistance to strain of the coating on a selectedregion may be increased by including at least one primer layer on thefirst section. In general, a “primer layer” is a coating layer on asurface that improves the adhesion of subsequent coating layers on thesurface. In some embodiments, the primer layer may include one or morepolymers.

As noted above, the presence of an active agent in a polymeric matrixcan interfere with the ability of the matrix to adhere effectively tothe surface of the device. Increasing the quantity of the active agentreduces the effectiveness of the adhesion. High drug loadings in thecoating can hinder the retention of the coating on the surface of thedevice. A primer layer can serve as a functionally useful intermediarylayer between the surface of the device and an active agent-containingor reservoir coating, or between multiple layers of reservoir coatings.The reservoir layer may include one or more active agents dispersedwithin one or more polymers. The primer layer provides an adhesive tiebetween the reservoir coating and the device—which, in effect, wouldalso allow for the quantity of the active agent in the reservoir coatingto be increased without compromising the ability of the reservoircoating to be effectively contained on the device during delivery and,if applicable, expansion of the device.

Some of the embodiments of polymer coatings are illustrated by FIGS.11A-D. The figures have not been drawn to scale, and the thickness ofthe various layers have been over or under emphasized for illustrativepurposes. FIG. 11A depicts a substrate of a medical device 500, such asa stent, having a surface 505. A primer layer 510 is deposited onsurface 505. The polymer in primer layer 510 may be a homopolymer,copolymer, terpolymer, etc. The polymer may also include random,alternating, block, cross-linked, blends, and graft variations thereof.For instance, primer layer 510 may include a poly(lactic acid).

FIG. 11B depicts a reservoir layer 515 deposited on surface 505. Thereservoir layer may have a polymer and an active agent 520 dispersed inthe polymer. The active agent may be, for example,40-O-(2-hydroxy)ethyl-rapamycin, known by the trade name of Everolimus,available from Novartis as Certican™. Reservoir layer 515 may releasethe active agent when substrate 500 is inserted into a biological lumen.Without a primer layer between surface 505 and reservoir layer 515,reservoir layer 515 may be more susceptible to failure as substrate 500is implanted in a patient for treatment.

FIG. 11C depicts reservoir layer 515 deposited on primer layer 510.Primer layer 510 serves as an intermediary layer for increasing theadhesion between reservoir layer 515 and surface 505. Increasing theamount of active agent 520 admixed within the polymer can diminish theadhesiveness of reservoir layer 515 to surface 505. Accordingly, usingan active agent-free polymer as an intermediary primer layer 510 allowsfor a higher active agent content for reservoir layer 515.

The coating may also have multiple primer and reservoir layers with thelayers alternating between the two types of layers through the thicknessof the coating. For instance, FIG. 11D depicts substrate 500 with aprimer layer 525 deposited on surface 505, followed by reservoir layer530 deposited on primer layer 525. A second primer layer, primer layer535, can then be deposited on reservoir layer 530. Reservoir layer 540is deposited over primer layer 535. Reservoir layers 530 and 540 haveactive agent 520 dispersed within the polymer. The different layersthrough the thickness of the coating can contain the same or differentcomponents. For instance, primer layers 525 and 535 can contain the sameor different polymers. Furthermore, reservoir layers 530 and 540 cancontain the same or different polymers or active agents.

By way of example, and not limitation, primer layer 510 in FIG. 11C canhave any suitable thickness, examples of which can be in the range ofabout 0.1 to about 10 microns, more narrowly about 0.1 to about 2microns. Reservoir layer 515 in FIG. 11C can have a thickness of about0.1 microns to about 10 microns, more narrowly about 0.5 microns toabout 2 microns. The amount of the active agent to be included onsubstrate 500 can be further increased by applying a plurality ofreservoir layers 515 on top of one another.

The primer layer can be formed by applying a polymer or prepolymer tothe stent by conventional methods. For example, a polymer or aprepolymer can be applied directly onto a medical device substrate inthe form of a powder or by vapor deposition. In one embodiment, anunsaturated prepolymer (e.g., an unsaturated polyester or acrylates) isapplied to the device, and then heat treated to cause the prepolymer tocrosslink.

The polymer or prepolymer can also be applied by depositing a polymercomposition onto the medical device. The polymer composition can beprepared by combining a predetermined amount of a polymer or aprepolymer and a predetermined amount of a solvent or a combination ofsolvents. The mixture can be prepared in ambient pressure and underanhydrous atmosphere. If necessary, a free radical or UV initiator canbe added to the composition for initiating the curing or cross-linkingof a prepolymer. Heating and stirring and/or mixing can be employed toeffect dissolution of the polymer into the solvent. The composition canthen be applied by conventional methods such as by spraying thesubstrate of the medical device with the composition.

The polymers used for the primer material should have a high capacity ofadherence to the surface of a medical device, such as a metallic surfaceof a stent, or a high capacity of adherence to a polymeric surface suchas the surface of a stent made of polymer, or a previously applied layerof polymeric material.

Various methods may be used to selectively heat selected regions of andto selectively apply materials on a medical device. For selectivelyapplying materials or coatings, a controlled deposition system can beused that applies various substances only to certain targeted portionsof a medical device. A representative example of such a system, and amethod of using the same, is described in U.S. Pat. No. 6,395,326 toCastro et al. A controlled deposition system can be capable ofdepositing a substance on a medical device having a complex geometry,and otherwise apply the substance so that coating is limited toparticular portions of the device. The system can have a dispenserand/or holder that support a substrate of a medical device. Thedispenser and/or holder can be capable of moving in very smallintervals, for example, less than about 0.001 inch. Furthermore, thedispenser and/or holder can be capable of moving in the x-, y-, orz-direction, and be capable of rotating about a single point.

The controlled deposition system can include a dispenser assembly. Thedispenser assembly can be a simple device including a reservoir whichholds a composition prior to delivery, and a nozzle having an orificethrough which the composition is delivered. One exemplary type ofdispenser assembly can be an assembly that includes an ink-jetprinthead. Another exemplary type of a dispenser assembly can be amicroinjector capable of injecting small volumes ranging from about 2 toabout 70 mL, such as NanoLiter 2000 available from World PrecisionInstruments or Pneumatic PicoPumps PV830 with Micropipette availablefrom Cell Technology System. Such microinjection syringes may beemployed in conjunction with a microscope of suitable design.

FIGS. 12 and 13 illustrate one set of embodiments of a controlleddeposition system. FIG. 12 depicts a stent 450 supported by a holderassembly 455 that may be coupled to a holder motion control system and anozzle 460 of a coating dispenser assembly 465. FIG. 11 illustratesanother view of the controlled deposition system in which dispenserassembly 465 remains stationary during deposition of a coatingcomposition 470. In this embodiment, nozzle 460 of dispenser assembly465 is positioned at a load position over, or in contact with, a strut475 of stent 450 as shown in FIG. 13. As composition 470 is deposited,dispenser assembly 465 remains stationary while stent 450 is moved viathe holder motion control system along a predetermined path beneath thestationary nozzle 460, thereby causing composition 470 to be depositedin a preselected geometrical pattern on stent 450. In another set ofembodiments, dispenser assembly 465 moves along a predetermined pathwhile holder assembly 455 remains stationary during deposition ofcomposition 470. In still another set of embodiments, both dispenserassembly 465 and holder assembly 455 move along respective predeterminedpaths during deposition of composition 470.

Additionally, in a similar manner, a controlled heating system mayselectively heat selected regions of a medical device such as a stent.In one set of embodiments, the elements of the controlled depositionsystem described herein may be adapted for use in a controlled heatingsystem. In one embodiment, a heating assembly with a heating apparatussuch as a laser or a heated filament may be used rather than a dispenserassembly with a nozzle. The heating assembly may remain stationary whilea stent is moved via a holder motion control system along apredetermined path beneath a stationary heating apparatus, therebyheating a preselected geometrical pattern on a stent. In anotherembodiment, the heating assembly may also be configured to move whilethe stent remains stationary. Additionally, both the heating assemblyand the stent may be moved.

The substances of the present invention can also be selectivelydeposited by an electrostatic deposition process. Such a process canproduce an electrically charged or ionized coating substance. Theelectric charge causes the coating substance to be differentiallyattracted to the device, thereby resulting in higher transferefficiency. The electrically charged coating substance can be depositedonto selected regions of the device by causing different regions of thedevice to have different electrical potentials.

Furthermore, selective coating of an implantable medical device may beperformed using photomasking techniques. Deposition and removal of amask can be used to selectively coat surfaces of substrates. Maskingdeposition is known to one having ordinary skill in the art.

While particular embodiments of the present invention have been shownand described, it will be obvious to those skilled in the art thatchanges and modifications can be made without departing from thisinvention in its broader aspects. Therefore, the appended claims are toencompass within their scope all such changes and modifications as fallwithin the true spirit and scope of this invention.

1. A method of manufacturing a stent, comprising: selectively heating aselected region of a scaffolding of a stent made of a polymer to modifya material property in the selected region of the scaffolding that has avariable strain profile under applied stress, wherein the modificationaccommodates the variable strain profile of the scaffolding by reducingor preventing mechanical instability when the scaffolding is underapplied stress, and wherein the scaffolding of the stent includes anetwork of interconnecting struts, wherein the scaffolding is formed bylaser cutting the network into a tube made of the polymer, wherein theregion includes a portion of a surface of the scaffolding, and whereinselectively heating the selected region of the scaffolding comprisesapplying heat to the surface of the scaffolding, the heat being appliedwithout dispensing material on the surface.
 2. The method of claim 1,further comprising cooling the selectively heated region.
 3. The methodof claim 1, wherein the polymer is bioabsorbable.
 4. The method of claim1, wherein the selected region comprises a higher strain than otherregions of the stent when the stent is placed under an applied stressduring use.
 5. The method of claim 1, wherein the selected regioncomprises a lower strain than other regions of the stent when the stentis placed under an applied stress during use.
 6. The method of claim 1,wherein the selected region is a portion of a straight portion of astrut of the stent that experiences no or relatively no strain when thestent is placed under an applied stress, wherein the selective heatingincreases the modulus of the selected region.
 7. The method of claim 1,wherein the selected region is a portion of a curved or bent portion ofa strut of the scaffolding of the stent that bends when the stent iscrimped or expanded which causes strain in the portion, wherein theselective heating decreases the modulus and increases the flexibility ofthe selected region.
 8. The method of claim 7, wherein the portionincludes abluminal, luminal, and/or side-wall surfaces of a concave partof the portion.
 9. The method of claim 7, wherein the portion includesabluminal, luminal, and/or side-wall surfaces of a convex part of theportion.
 10. The method of claim 7, wherein the selected region is assmall as 20 microns in diameter.
 11. The method of claim 7, wherein theselected region is as small as 60 microns in diameter.
 12. The method ofclaim 7, wherein the scaffolding is completely made from a biodegradablepolymer or combination of biodegradable polymers.
 13. The method ofclaim 1, wherein the selective heating is performed with a laser and/orby conduction.
 14. The method of claim 1, wherein the material propertyis the modulus of the polymer in the region which is increased by theselective application of heat.
 15. The method of claim 1, wherein thematerial property is the modulus of the polymer in the region which isdecreased by the selective application of heat.
 16. The method of claim1, wherein the selected region is heated to greater than or equal to theglass transition temperature of the polymer and less than or equal tothe melting temperature of the polymer to increase a modulus of theselected region due to crystallization of the polymer in the selectedregion.
 17. The method of claim 1, wherein the selected region is heatedto greater than the melting temperature of the polymer and quenched to atemperature below the glass transition temperature of the polymer todecrease a modulus and increase the flexibility of the selected region.18. The method of claim 17, wherein the polymer in the selected regionis amorphous after quenching.
 19. The method of claim 1, wherein theselected region is heated to greater than the melting temperature of thepolymer, allowed to cool to a temperature between the glass transitiontemperature and the melting temperature of the polymer to allowcrystallization in the selected region followed by quenching theselected region to a temperature below the glass transition temperature.